1. Field of the Invention
The present invention relates to methods and apparatus for the administration of testosterone and other androgens. More particularly, the present invention relates to using controlled heat to improve administration of testosterone pharmaceuticals.
2. Description of the Prior Art
The dermal administration of pharmaceutically active compounds involves the direct application of pharmaceutically active formulation(s) to the skin, wherein the skin absorbs a portion of the pharmaceutically active compound which is then taken up by the blood stream. Such administration has long been known in the practice of medicine and continues to be an important technique in the delivery of pharmaceutically active compounds. For example, U.S. Pat. No. 4,286,592, issued Sep. 1, 1981, to Chandrasekaran shows a bandage for administering drugs to a user""s skin consisting of an impermeable backing layer, a drug reservoir layer composed of a drug and a carrier, and a contact adhesive layer by which the bandage is affixed to the skin.
For some drugs, such dermal administration offers many important advantages over other delivery techniques, such as injection, oral tablets, and capsules. These advantages include being noninvasive (thus, less risk of infection), avoiding first pass metabolism of the drug in the liver when the drug is taken orally and absorbed through the gastrointestinal tract, and improved control of the concentration of pharmaceutically active compounds in a patient""s bloodstream. In particular, uncontrolled and unwanted variance in concentrations over time are typical in injection and oral administrations and are often associated with undesirable side effects and/or less than satisfactory intended effects.
In recent years there has been an increased interest in noninvasive drug delivery systems such as androgen transdermal therapeutic systems (ATTS). ATTSs offer the advantages of providing controlled release of a drug for a specified period, in contrast to the uncontrolled peaks and troughs produced by oral or parenteral application. Other advantages of these systems include: elimination of gastrointestinal absorption, reduced total dosage, less expensive than intramuscular or intravenous administration where applicable, avoidance of xe2x80x9cfirst passxe2x80x9d inactivation by the liver, use of agents with a narrow therapeutic index, and improved compliance with decreased administration cycle.
The major goals of testosterone replacement therapy are to restore serum testosterone concentrations to within the normal range for healthy men and, if possible, in a way that mimics the normal circadian pattern of endogenous secretion. More specifically it is desirable for the therapy to mimic the natural rise of testosterone level which peaks in the morning followed by gradual decrease, reaching a valley in the evening. Use of a androgen transdermal delivery system to deliver testosterone as disclosed in the present invention in hypogonadal men can achieve this goal. Other therapeutic uses of androgen(s) with the present invention include but are not limited to treatment of hypopituitarism, osteoporosis, menstrual disorders, refractory anemia, promotion of anabolism, and influencing conditions related to puberty.
Male hypogonadism is a disorder whereby testosterone production is reduced below the normal range of 3 to 10 mg/day. Symptoms of this disorder include impairment in:libido, sexual function, energy, mood, as well as regression of secondary sex characteristics and decreases in lean body mass and bone density. Available androgen replacement modalities include intramuscular injection of long-acting testosterone esters and oral administration of alkylated and esterified testosterone. However, neither of these treatments delivers testosterone in a manner which produces plasma levels mimicking normal circadian profiles of the endogenous hormone. Recently several transdermal testosterone systems have been developed. These systems have normalized serum testosterone concentrations over a period of 24 hours and allowed some approximation of the circadian pattern seen in healthy young men. Although these systems have proven useful, they are not without side effects. For example approximately 53 percent of men experience local skin reactions (contact dermatitis) at the application sites after using Androderm(copyright), a testosterone patch, which in some instances necessitates discontinuing use of the patch.
The term xe2x80x9candrogen transdermal therapeutic systemxe2x80x9d or xe2x80x9cATTS,xe2x80x9d as used herein, is defined as an article, apparatus or method for delivery of androgen into the human body via skin permeation. An ATTS is designed for therapeutic and other uses of androgens. The term xe2x80x9cATTSxe2x80x9d in this application, unless otherwise specified, only refers to those systems in which the main driving force for drug permeation is the drug concentration gradient.
The term xe2x80x9candrogen,xe2x80x9d as used herein, is broadly defined to include any pharmaceutically active compound which is capable of regulating masculine secondary sexual characteristics, including but not limited to esters of testosterone such as propionate, phenylacetate, enanthate, cypionate, methyl testosterone, fluoxymesterone, methandrostenolone, 17 alpha-methylnortestosterone, norethandrolone, stanolone, oxymetholone, stanozolol, ethylestrenol.
Additionally, androgens include pharmaceutically active agents which promote growth, such as an increase in height and development of skeletal musculature, thickening of the skin, proliferation of sebaceous glands, as well as loss of subcutaneous fat, growth of axillary and body hair, growth of the larynx, growth of beard and initiating the onset of male pattern baldness. Androgens may also be generally described as pharmaceutical agents acting on the pituitary, testes and sebaceous glands or an agent which has nitrogen retaining anabolic effects.
The term xe2x80x9cskin,xe2x80x9d as used herein, is defined to include stratum corneum covered skin and mucosal membranes.
In an ATTS, an androgen is usually contained in a formulation, such as a hydro-alcohol gel, and may include a rate limiting membrane between the formulation and skin for minimizing the variation in the permeation of the androgen. When an ATTS is applied to skin, the androgen begins to transport out of the formulation, and transport across the rate limiting membrane (if present). The androgen then enters the skin, enters the blood vessels and tissues under the skin, and is taken into the systemic circulation of the body by the blood. An ATTS may have certain amounts of androgen in or on the skin side (the bottom side) of the rate limiting membrane (if present) prior to use. For example, some of the drug may be present in an adhesive on the bottom side of the rate limiting membrane. In those ATTS""s, that portion of the androgen on the skin side of the rate limiting membrane will enter the skin without passing through the rate limiting membrane.
After placing an ATTS on the skin, the androgen concentration in the blood typically remains unchanged from the natural levels for a period of time, before starting to gradually increase and reach a concentration deemed to be medicinally significantly beneficial, called the xe2x80x9ctherapeutic levelxe2x80x9d (the time it takes to reach the therapeutic level is referred to hereinafter as the xe2x80x9conset time.xe2x80x9d). The onset time and the delivery rate of the androgen into the targeted area(s) of the body for a typical ATTS are usually determined by several factors, including: the rate of release of the androgen from the formulation, the permeability of the androgen across the rate limiting membrane (if a rate limiting membrane is utilized), the permeability of the androgen across the skin (especially the stratum corneum layer), androgen storage in and release from the depot sites, the permeability of the walls of the blood vessels, and the circulation of blood and other body fluid in the tissues (including the skin) under and around the ATTS.
While an ATTS works well in many aspects, current dermal androgen delivery technology has some serious limitations, including: 1) the long onset time; 2) the skin permeability being so low so that a strong permeation enhancing agent has to be used to increase skin permeability, which tends to cause serious skin irritation.
It is known that elevated temperature can increase the absorption of drugs through the skin. U.S. Pat. No. 4,898,592, issued Feb. 6, 1990, to Latzke et al., relates to a device for the application of heated transdermally absorbable active substances which include a carrier impregnated with transdermally absorbable active substance and a support. The support is a laminate made up of one or more polymeric layers and optionally includes a heat conductive element which is used for distribution of the patient""s body heat such that absorption of the active substance is enhanced. U.S. Pat. No. 4,230,105, issued Oct. 28, 1980, to Harwood, discloses a bandage with a drug and a heat-generating substance, preferably intermixed, to enhance the rate of absorption of the drug by a user""s skin. Separate drug and heat-generating substance layers are also disclosed. U.S. Pat. No. 4,685,911, issued Aug. 11, 1987, to Konno et al., discloses a skin patch including a drug component, and an optional heating element for melting the containing formulation if body temperature is inadequate to do so.
However, it would be advantageous to develop methods and apparatus to improve the androgen administration of ATTSs, to better accommodate various clinical needs, and to minimize side effects. For example it would be advantageous to develop a drug delivery system that can elevate skin temperature to a desired temperature range. The desired temperature range should be a range which improves the administration of the androgen, but does not significantly increase the chances of trauma to the skin due to overheating. Similarly it would be advantageous to provide elevated temperatures within a prescribed range which can be altered or adjusted within the range as needed. Having an adjustable temperature would allow a patient or caregiver greater control over the absorption rate. Furthermore it would also be advantageous to provide an elevated temperature for a controlled period of time or a desired duration. It would also be advantageous to develop a method and apparatus to allow the patient or caregiver to freely select the site on the skin where temperature is to be elevated.
The present invention relates to the methods and apparatus for improving transdermal administration of testosterone pharmaceuticals through the use of controlled heat.
In the application of an androgen transdermal therapeutic system, such as the Androderm(copyright) (testosterone transdermal system manufactured by TheraTech, Inc., the absorption of the androgen is usually determined by a number of factors including: the diffusion coefficient of androgen molecules in the drug formulation, the concentration of dissolved androgen in the formulation, the skin permeability to the androgen, androgen storage in and release from the depot sites (sites in the skin and/or sub-skin tissues in which dermally-absorbed androgen molecules are stored before being gradually released into other parts of the body), the body fluid (including blood) circulation in the skin and/or other tissue under the skin, and permeability of the walls of capillary blood vessels in the sub-skin tissues. Thus, in order to address the limitations of the current dermal androgen delivery technologies, it is desirable to have control over and have the capability to favorably influence these factors. It is believed that controlled heating can potentially favorably affect each one of the above factors for more efficient delivery of androgen.
Specifically, increased temperature generally can increase diffusion coefficients of the androgens in the formulations and their permeability across the skin. Increased heat also increases the blood and/or other body fluid flow in the tissues under the ATTS, which should carry the drug molecules into the systemic circulation at faster rates. Additionally, increased temperature also increases the permeability of the walls of the capillary blood vessels in the sub-skin tissues. Thus, the present invention uses controlled heating to affect each of the above factors for obtaining controllable dermal absorption of androgens.
Skin irritation is a major problem with ATTSs currently on the market. The skin irritation is believed to be mainly caused by a permeation enhancer in the formulation. (In the case of Androderm(copyright), the permeation enhancer is monoglyceral oleate). The permeation enhancer is needed to increase skin permeability so that sufficient testosterone can permeate across the skin. The degree of skin irritation is usually positively correlated with the permeation enhancer concentration in the formulation and contact time with the skin. Since controlled heat can significantly increase dermal skin absorption, it is conceivable that, with controlled heat, one may be able to reduce the concentration of the enhancer in the formulation, reduce the contact time between the formulation and the skin, and/or use a milder permeation enhancer. Properly doing so should reduce skin irritation while still delivering sufficient testosterone. In other words, using controlled heat can shift at least some burden to enhance skin permeability from permeation enhancer to heat, which is a much safer way to enhance skin permeability.
This invention provides novel methods and apparatus for controlled heating (hereinafter xe2x80x9ctemperature control apparatusxe2x80x9d) during the application of the ATTS, such that heating can be initiated, maintained and terminated to accommodate the patient""s needs. Through the proper selection of the moment(s) to initiate controlled heating, the heating temperature, the moment(s) to increase or decrease the temperature, and moment(s) to stop the controlled heating, the following control/manipulation of the absorption rates can be achieved: 1) the onset time of the androgen in the ATTS can be shortened; and 2) the androgen absorption rate throughout a selected period of duration or throughout the entire duration of the ATTS application can be increased.
The present invention also relates to methods and apparatus for using an insulating device, such as a cover made of insulating material (i.e. closed-cell foam tape) with adhesive edges, and a size slightly larger than the ATTS to cover the ATTS when the ATTS and the skin of the user is exposed to extreme temperature (i.e. hot shower or hot tub bath; direct sunshine).
One of the more important aspects of the present invention is the apparatus for generating and providing controlled heating. The controlled heat generating apparatus generally comprises temperature regulating mechanism such as a heat generating medium and means to pass the heat generated by the heat generating medium to the ATTS, the skin, and/or the sub-skin depot and storage sites. A controlled heat generating apparatus generally further includes a mechanism (such as tape, adhesive, and the like) for affixing the apparatus onto the ATTS and/or the skin. Preferably, the affixation mechanism securely holds the controlled heat generating apparatus in place while in use, but also allows relatively easy removal after use. Additionally, the controlled heat generating apparatus may further include a mechanism for reducing and/or terminating the generation of heat. When the heat generating apparatus is used in conjunction with an ATTS, the shape and size of the controlled heat generating apparatus may be specially made to accommodate the ATTS with which they are to be employed.
Controlled elevation of skin temperature provides specific advantages over the prior art. For example, the present invention provides elevation of skin temperature within a predetermined temperature range. In one embodiment, this predetermined temperature range is made possible by providing an oxidation reaction within a compartment having a controlled permeability to oxygen. By varying the compartment""s permeability to oxygen, the temperature elevation caused by the oxidation reaction can be controlled or more precisely regulated within the predetermined narrow range. The duration of the elevated temperature can be controlled by removing the device entirely from the skin, by preventing oxygen from entering the compartment containing the oxidation reactants, or by providing a predetermined amount of oxidation reactants which will generate heat for a given amount of time when exposed to oxygen. Furthermore the heating site may be freely selected where the heating apparatus is not incorporated with the ATTS. Thus, the present invention provides controlled heating.
One embodiment of a temperature control apparatus is a shallow chamber including air impermeable side wall(s), a bottom wall, and an air impermeable top wall which has area(s) with limited and desired air permeability (e.g., holes covered with a microporous membrane or a membrane with a specific rate of permeability to oxygen). A heat generating medium is disposed within the shallow chamber. The heat generating medium preferably comprises a mixture of iron powder, activated carbon, salt, water, and, optionally, sawdust. The controlled heat generating apparatus is preferably stored in an airtight container from which it is removed prior to use. After removal from the airtight container, oxygen in the atmosphere (xe2x80x9cambient oxygenxe2x80x9d) flows into the heat generating medium through the areas on the air impermeable top with desired air-permeability to initiate a heat generating oxidation reaction (i.e., an exothermic reaction). The desired heating temperature and duration can be obtained by controlling the flow air through the top (e.g., selecting the right size and number of holes on the cover and/or selecting the microporous membrane covering the holes for a specific air permeability), and/or by selecting the right quantities and/or ratios of components of the heat generating medium. Air flow through the sides of the chamber may be additionally or alternatively controlled in like manner.
This embodiment of the controlled heat generating apparatus preferably includes a mechanism for affixing the controlled heat generating apparatus onto the skin or an ATTS that is applied to the skin. For applications where the removal or termination of the heating might be necessary, the heat generating apparatus may also have a mechanism for allowing easy removal from the ATTS and/or the skin or for termination of the heating. One mechanism for allowing easy removal of the heat generating apparatus from an ATTS without removing the ATTS from the skin comprises a layer of adhesive on the side walls of the heat generating apparatus with an nonadhesive area or less adhesive area (less adhesive than the adhesive affixing the ATTS to the skin) at the bottom of the shallow chamber. The non- or less adhesive area may have a shape similar to that of the ATTS. When such a heat generating apparatus is applied onto the ATTS which is on the skin, the adhesive at the bottom of the side walls of the heat generating apparatus adheres to the skin, and non- or less adhesive part is on top of, but not adhered or not strongly adhered to the ATTS. This allows for removal of the heat generating apparatus without disturbing the ATTS.
In the present invention, means for preventing heat loss is also provided. Means for preventing heat loss includes insulating materials used in the drug delivery and temperature control components. Other means for preventing heat loss include using adhesives and other means for securing and sealing the heat generating apparatus patch to the skin of the user and the ATTS so that heat does not escape through unsecured edges or corners of the drug delivery system, as well as customized shaping or molding of the heat generating apparatus patch to more appropriately fit an ATTS or a specific part of the user""s body. For example, a heat generating apparatus patch may have a substantially oval shape. The oval shape facilitates the prevention of heat loss through unsecured corners by eliminating corners which may be difficult to secure and result in heat loss.
Another embodiment of the present invention provides a foam cover for the heat generating apparatus patch. The foam tape cover has insulative properties which help to prevent heat loss through the cover and which help to prevent varying ambient temperatures from adversely affecting the heat generated by the heat generating apparatus patch. Moreover, an insulative cover capable of insulating the exposed surfaces of the heat generating apparatus patch and ATTS is also contemplated.
Although one application of such a heat generating apparatus is to be used in connection with an ATTS, it is understood that the heat generating apparatus can also be applied directly to the skin to increase the release of drugs from depot sites or sites of injection or implantation of controlled released drugs (storage sites), or to accelerate the absorption of subcutaneously or intramuscularly injected androgens.
The heat generating mechanism of the present invention for the controlled heat generating apparatus is not limited to the preferred exothermic reaction mixture of iron powder, activated carbon, salt, water, and, optionally, sawdust, but may include a heating unit whose heat is generated by other exothermic chemical reactions.
Similarly, an electric heating unit may be used. The electric heating unit, preferably, includes a two dimensional surface to pass the heat to the ATTS and/or the skin. The electric heating unit may also include a temperature feedback system and temperature sensor that can be placed on the ATTS or the skin. The temperature sensor monitors the temperature at the ATTS or skin and transmits an electric signal based on the sensed temperature to a controller which regulates the electric heating unit to keep the temperature at the ATTS or skin at desired levels. Preferably, a double sided adhesive tape can be used to affix the electric heating unit onto the skin.
The heat generating mechanism may also comprise an infrared generating unit and mechanism to direct the infrared radiation onto the ATTS or the skin. It may also have a temperature feedback system and temperature sensor that can by placed on an ATTS or the skin to control the intensity of the infrared emission in order to maintain the temperature at the ATTS or skin at desired levels.
The heat generating mechanism may further comprise a microwave generation unit and a mechanism to direct the microwave radiation onto the ATTS or the skin. Again, the heat generating mechanism may have a temperature feedback system and a temperature sensor to regulate the intensity of the microwave emission to maintain the temperature at the ATTS or skin at desired levels.
It is an object of some embodiments of the present invention to provide an apparatus for increasing the diffusion coefficient of androgen molecules in drug formulations used in a transdermal drug delivery system.
It is an additional object of some embodiments of the present invention to provide a method and apparatus for increasing the skin permeability to the androgen of a transdermal drug delivery system.
It is yet another object of some embodiments of the present invention to provide a method and apparatus for manipulating the storage and release of the androgen from depot sites with controlled heat.
It is yet a further object of one embodiment of the invention to provide a method and apparatus for increasing body fluid circulation near a drug delivery site thereby increasing entrance of a drug formulation into systemic circulation with controlled heat.
It is yet an additional object of some embodiments of the present invention to provide a method and apparatus for increasing the permeability of the walls of capillary blood vessels in subskin tissues for facilitating uptake of dermally absorbed androgen into the systemic circulation.
It is still another object of some embodiments of the present invention to reduce the concentration of a permeation enhancer used in a transdermal drug delivery system and reduce contact time between the skin of a patient and the drug formulation used in a transdermal drug delivery system, particularly a system having a permeation enhancer, while still delivering a sufficient amount of androgen via skin permeation.
It is still further an object of some embodiments of the present invention to provide a method and apparatus for using a mild permeation enhancer in a transdermal drug delivery system while still delivering sufficient androgen.
It is still an additional object of one embodiment of present invention to provide a method and apparatus for shifting the burden to enhance permeability and improve performance of a transdermal drug androgen system from the permeation enhancer to heat.
It is another object of some embodiments of the present invention to provide a method and apparatus which can more closely mimic circadian patterns as they relate to androgen concentration within the blood stream.